Sjogren's syndrome is a human autoimmune disease of the salivary and lacrimal glands resultIng in debilitating xerostomia (dry mouth) and xerophthalmia (dry eyes). This disease may present as either a primary autoimmune disease or as a secondary autoimmune disease concomitant with other connective tissue diseases or diabetes. Although classified as an orphan disease, it is grossly under-diagnosed; thus, it is estimated that as many as 2-4 million individuals (90% of which are women) actually have a form of the disease. At present, diagnosis of Sjogren's syndrome involves detection of lymphocytic infiltrates in biopsies of the labial glands, the presence of autoantibodies to rheumatoid factor and cellular components (e.g., SS-A/Ro, SS-B/La, alpha-fodrin and nuclear material), hypergammaglobulinemia, and loss of exocrine gland flow rates following stimulation. None of these markers is, by itself, disease specific. Recently, we and others have shown that all sera from patients with confirmed Sjogren's syndrome contain an autoantibody to the muscarinic cholinergic-3 receptors (M3) expressed on exocrine gland cells. This finding presents the possibility that this single marker may be able to define autoimmune exocrinopathy. Thus, we propose to investigate the feasibility of developing a simple, non-invasive diagnostic test capable of identifying patients with Sjogren's syndrome. Specific aims of this phase STTR grant are i) to determine if Sjogren's syndrome patients can be identified specifically and universally with an ELISA test using a full-length recombinant form of the M3 protein, and 2) compare the results from ELISA testing with those obtained utilizing a M3-expressing, transfected COS-7 cell line. If results of this study confirm and expand our preliminary data, then final development of a simple, non-invasive, Sjogren's syndrome-specific diagnostic test would be a welcome addition to the clinical diagnostic laboratory and the patient. PROPOSED COMMERCIAL APPLICATIONS: Identification of autoantibodies against the muscarinic acetylcholine-3 receptor (M3) on exocrine gland cells now appears to be the best single marker of autoimmunity in Sjogren's syndrome (autoimmune exocrinopathy). While Sjogren's syndrome is classified an orphan disease, it is also recognized as being under-diagnosed; thus, there may be perhaps 2-4 million patients in the US, 90% of which are women. Development of a non-invasive diagnostic test based on detection of M3 autoantibody would be a major advancement for the clinical laboratory.